Single-use manifold and sensors for automated, aseptic transfer of solutions in bioprocessing applications

ABSTRACT

Presteralized manifolds are provided which are designed for sterile packaging and single-use approaches. Disposable tubing and flexible-wall containers are assembled via aseptic connectors. These manifolds interact with valves and pumping equipment which can be operated by a controller which provides automated and accurate delivery of biotechnology fluid. The manifold also being used in conjunction with one or more conductivity sensors used to measure the conductivity of the biotechnology fluid. Such sensors interact with the controller or are connected to a separate user interface. The combination of disposable tubing, flexible-wall containers, aseptic connectors, manifold, controller, and conductivity sensors provides an aseptic environment while avoiding or reducing cleaning and quality assurance procedures.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of application Ser. No. 10/764,624, filedJan. 26, 2004, now U.S. Pat. No. 7,052,603, which is a divisional ofapplication Ser. No. 10/172,083, filed Jun. 14, 2002, now U.S. Pat. No.6,712,963, each incorporated by reference hereinto.

FIELD OF THE INVENTION

The invention generally relates to the aseptic transfer of solutions outof one or more biological fluid and/or process fluid storage or supplycontainers. Single-use manifold systems carry out transfers needed inbioprocessing applications. With the invention, automated dispensing isaccomplished, preferably in association with one or more disposableconductivity sensors and often with one or more remotely controlledpinch valves.

BACKGROUND OF THE INVENTION

Good manufacturing practices and governmental regulations are at thecore of any pharmaceutical, biotechnology and bio-medical manufacturingprocess or procedure. Such manufacturing processes and procedures aswell as associated equipment must undergo mandated, often lengthy andcostly validation procedures. Similar issues exist for sensors whenneeded in such systems, such as conductivity sensors.

For example, the equipment used for the separation and purification ofbiomedical products must for obvious reasons, meet stringent cleanlinessrequirements. The cleaning validation of new or re-commissionedpurification equipment (including sensor equipment such as equipment forpreparative chromatography or tangential flow filtration) may require asmany as 50 test-swabs of exposed surfaces and subsequent biologicalassays of such test-swabs. For a single piece of purification equipment,the associated and reoccurring cost of a single cleaning validation mayreadily exceed multiple thousands of dollars.

To reduce such cleaning validation costs and expenses, and/or to reducethe occasions when cleaning is needed or required, the pharmaceuticaland biotech industries are increasingly employing, pre-sterilized,single-use, plastic tubing and collapsible, plastic bags for solutiontransfer and storage. Sterilization is accomplished by exposing thecomplete tube/bag manifold to gamma irradiation, or to an ethylene oxideatmosphere. The pre-sterilized, aseptically packaged tube/bag manifoldsare commercially available (currently from TC Tech; HyClone; St GobainPerformance Plastics, for example) and are used for the manual transferof solutions. Typically, the solution transfer procedure requires atechnician to operate a peristaltic pump and to manually open and closetube clamps for diverting the solution from the reservoir to the storagebags. Although this procedure reduces the cleaning efforts and cleaningvalidation expense, operator interaction and time still are required,and these approaches are dependent upon operator expertise forconsistent accuracy and precision.

Dispensing approaches having automated features (which can includesensors, monitors and programmable controllers) are generally known.Keys et al. U.S. Pat. No. 5,480,063 and U.S. Pat. No. 5,680,960 describefluid dispensing units which control fluid volumes in conjunction with aclosed loop approach, which these patents suggest can avoid the need forventing. The fluid to be dispensed exits the closed loop apparatusthrough a fill tube, as directed by a controller. Such approaches do notaddress the cleaning needs and/or cleaning validation costs andexpenses, were these types of systems to be used in pharmaceutical andbiotech industries for dispensing, directing, combining or separatingbiological or chemical fluids.

Prior systems can incorporate diaphragm valves, which come into directcontact with the process solution, and these valves are a potentialsource of contamination. Thus diaphragm valves require costly cleaningvalidation procedures. In addition, such systems typically lack suitablesensors, especially conductivity sensors.

It has been found that, by proceeding in accordance with the presentinvention, significant cost savings and better performance can berealized in a system which incorporates automated, aseptic manifolds andsensors within the field of technology which embraces pre-sterilized,single-use plastic tubing and containers having at least one collapsibleportion. The components and sensors which contact the biological orchemical fluid are each presterilized and disposable after use.

SUMMARY OF THE INVENTION

The present invention is directed to manifold units which include atleast one sensor and which are presterilized and disposable, making themsingle-use units which are sterilized and packaged so as to be usable“off the shelf” and which thus directly address the problem of tediousand time consuming cleaning and testing at the use site. Multipleembodiments are disclosed. Each includes tubing lengths, at least onesensor and a plurality of single-use storage or collection bags, eachhaving multiple inlet and/or outlet passages which are selectivelyopenable and closeable. The tubing lengths can interact with one or morepinch valves which are operable remotely. Remote operation is automatedby a controller programmed to carry out procedures according to aselected embodiment.

It is a general aspect or object of the present invention to provideimproved single-use manifolds with at least one sensor for automated,aseptic transfer of solutions in bio-processing or chemical processingapplications.

Another aspect or object of the present invention is to provide improvedapparatus and method which combine pinch valve use with disposable,sterilized manifold dispenser units that incorporate at least onedisposable sensor.

Another aspect or object of this invention is to provide improvedapparatus and method which greatly reduce the expenditure of time andresources devoted to cleaning procedures for transfer equipment used inpharmaceutical and biological industries and laboratories wherecontamination of biological and/or chemical fluids cannot be tolerated.

An aspect or object of the present invention is to reduce the need forvalidation procedures for equipment used in separation and purificationof fluids such as in conjunction with the preparation, separation,sensing and dispensing of bio-medical products.

Another aspect or object of this invention is that it handlescleanliness requirements for procedures including a sensing function,such as fluid dispensing, preparative chromatography and tangential flowfiltration while automating operation thereof.

Another aspect or object is to integrate disposable conductivity sensorswith the equipment used in the separation and purification of fluids.

Another aspect or object is to provide the ability to connect disposableconductivity sensors with either a system controller or a userinterface.

These and other objects, aspects, features, improvements and advantagesof the present invention will be clearly understood through aconsideration of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

In the course of this description, reference will be made to theattached drawings, wherein:

FIG. 1 is a somewhat schematic illustration of a single-use,presterilized system which is especially suitable for solution transferand collection;

FIG. 2 is an illustration of the single-use system of FIG. 1 inoperative association with pinch valves, at least one of which isremotely operable;

FIG. 3 is an illustration of the combination of the features of FIG. 1and FIG. 2, shown with means for use to transfer solution through thesystem;

FIG. 4 is a somewhat schematic illustration of a single-use,presterilized system which is especially suitable for use in automatedpreparative chromatography;

FIG. 5 is an illustration of the single-use system of FIG. 4 inoperative association with pinch valves, at least one of which isremotely operable;

FIG. 6 is an illustration of the combination of features of FIG. 4 andFIG. 5, shown with means for use in transferring solution through thesystem;

FIG. 7 is a somewhat schematic illustration of a single-use,presterilized system which is especially suitable for automatedtangential flow filtration procedures;

FIG. 8 is an illustration of the single-use system of FIG. 7 inoperational association with pinch valves, at least one of which isremotely operable;

FIG. 9 is an illustration of the combination of the features of FIG. 7and FIG. 8, shown with means for use to transfer solution through thesystem;

FIG. 10 is an illustration of the single-use system especially suitablefor solution transfer and collection in operational association with atleast one disposable conductivity sensor;

FIG. 11 is an illustration of the single-use system especially suitablefor use in automated preparative chromatography in operationalassociation with a disposable conductivity sensor;

FIG. 12 is an illustration of the single-use system especially suitablefor automated tangential flow filtration procedures in operationalassociation with at least one disposable conductivity sensor;

FIG. 13 is a cutaway view of a disposable conductivity sensor;

FIG. 14 is shows the exterior of a user interface;

FIG. 15 is an exemplarily flowchart of the different screens presentedby the user interface;

FIG. 16 is an exemplarily flowchart of the different screens presentedby the user interface when the user selects to run the recalibrationprogram; and

FIG. 17 is an exemplarily flowchart of the different screens presentedby the user interface when the user selects to view the calibration andproduction information.

DESCRIPTION OF THE PARTICULAR EMBODIMENTS

As required, detailed embodiments of the present invention are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely exemplary of the invention, which may be embodied in variousforms. Therefore, specific details disclosed herein are not to beinterpreted as limiting, but merely as a basis for the claims and as arepresentative basis for teaching one skilled in the art to variouslyemploy the present invention in virtually any appropriate manner.

A system particularly designed for use as an automated, aseptic solutiontransfer system is illustrated in FIGS. 1-3. Fluids processed accordingto this invention are variously referred to herein as biotechnologyfluids, pharmaceutical fluids, chemical fluids, and so forth. These areunderstood to be solutions, liquids, gas-including systems, and thelike. In general, these are referred to herein as biotechnology fluid orfluids.

In the pharmaceutical and biotechnology industries, media preparationdepartments typically prepare the solutions used in a solutionproduction protocal which follows good manufacturing practices. Mediapreparation departments are responsible for maintaining solutionrecipes, preparing and storing buffer solutions and other tasksdemanding consistency and accuracy. For example buffer solutions areprepared in large vats, then pumped through a sterilizing filter, suchas one having a porosity of 0.1μ. Typically such solutions need to befilled into presterilized, single use storage bags for later use. Amedia preparation department may also be responsible for providinginoculating solutions to the operators of a bioreactor. At thecompletion of a bioreactor batch, the reactor broth often is filled intosterile storage bags for later processing.

FIG. 1 shows single-use, presterilized components of the invention.Generally, these disposable components are a manifold and transfertubing assembly and a plurality of bags. A plurality of single-usestorage/collection bags 21, 22, 23 are shown. Each has three tubeconnections. The primary inlet tubing consists of an aseptic connector24 and a manual shut-off clamp 25, each of generally known construction.During solution storage, the aseptic connector is covered with an endcap (not shown) to protect the connector 24 from contamination. Themanual shut-off clamp 25 is closed during solution storage. These areshown on a first tube connection 30.

The second tube connection 26 consists of a short piece of tubingconnected to the bag with a closed manual shut-off clamp. This tubingand clamp arrangement is used to relieve any gas and/or pressurebuild-up inside the bag during the filling operation. The third tubeconnection 27 is identical to the second connection and includes a shortpiece of tubing and a clamp. This can be used as an auxiliary inletand/or outlet for recirculation of the bag contents.

During a typical bag-filling operation, the first and/or last collectionbag can serve the purpose of quality control bags. Often these qualitycontrol bags will be smaller in volume, such as one liter. During theinitial system priming cycle, the first such quality assurance (QA) bagis filled with process solution. At the end of the dispensing cycle whenall of the bags containing the product of the operation, usually largerin volume that the QA bag(s), have been filled, the second QA bag isfilled. The solutions contained in the QA bags are subsequently analyzedfor contamination or for other quality assurance needs.

When the bag-filling process is completed, the manual shut-off clamps oneach bag are closed and the aseptic tube connections are disconnected.During storage, the aseptic connector ends are protected with end caps(not shown).

Turning now to the single-use, sterilized manifold and transfer tubingassembly of FIG. 1, one such unit is generally shown at 28. Thisrepresents a generalized manifold for automated solution transfer. Aninlet end portion 29 of transfer tubing 31 of the unit 28 is forcommunication with a container, such as a vat, of solution, typicallysterile solution. Sterilized manifold and transfer tubing assembly 28 isshown with an optional, in-line pressure sensor 32 and a single-usesterilizing filter 33. An end portion having serially connected endportions are downstream of the illustrated filter 33. By a suitablemovement imparting device, solution moves from the vat or reservoirthrough the sensor 32 (if included) and filter 33 and then is seriallydiverted into the single-use, sterilized storage bags.

FIG. 2 shows a plurality of pinch valves 41, 42, 43 and their respectiverelative positions with respect to the storage bags. Some or all of thevalves can be operated remotely and typically will be pneumatically orelectrically activated. A typical set up will have capacity for up totwelve pneumatically actuated pinch valves or more. A like number ofstorage bags can be accommodated. FIG. 2 shows the relative positions ofthe pinch valves in association with the optional pressure sensor andthe single-use, sterilizing filter. FIG. 3 shows the relative positionof the manifold and transfer tubing assembly 28 with the vat 44 and thepump head of a pump unit 45. Preferably, the pump is a high-accuracy,low-shear peristaltic pump which provides gentle and reproducible bagfilling. An example is a Watson Marlow 620 RE peristaltic pump head.

Access to the storage bags is provided via the pinch valves. The pinchvalves are normally closed, and typical pneumatic pinch valves requirepressurized air (for example 80-100 psi) to open. When such a pinchvalve is pressurized, solution is allowed to enter the storage bag whilethe air in the bag escapes through an integral vent filter. The pinchvalve(s) are pneumatic or electrically operated pinch valves (currentlyavailable from ACRO Associates, Inc). They are installed external to thetubing and are operated by a multi-valve controller (currently availablefrom SciLog Inc.), or another computer-based process logic control (PLC)device. The external pinch valves divert the solution inside themanifold without compromising the sterile environment inside the tubing.Diaphragm valves used in other systems are in constant contact with theprocess solution, whereas pinch valves do not contact the processsolution.

The optional, disposable pressure sensor 22 continuously monitors thefilter back pressure. This sensor can provide information to a suitablecontroller to avoid undesired events. For example, a controller canissue an alarm when a safe, user-defined, pressure limit has beenexceeded, indicating that the capacity of the sterilizing filter hasbeen exhausted. Details in this regard are found in U.S. Pat. No.5,947,689 and No. 6,350,382 and in U.S. Patent Application PublicationNo. 2002/0043487. These patents and publications and all otherreferences noted herein are incorporated by reference hereinto.

The controller can be a stand-alone unit or be associated with anotherdevice. In a preferred arrangement, the controller is associated withthe pump unit 45. This is shown at 46 in FIG. 3. Whatever form it takes,the controller controls operation of the remotely operable pinchvalve(s). The batch filling rate as well as the batch volume deliveredinto each storage bag is user-programmable via software residing in thecontroller. The controller provides automated bag filling by volume,weight or based on filling time and pump rate.

Typically, a user-determined program will be provided for the automatedfilling of storage bags according to FIGS. 1-3. This is described interms of a SciPro controller of Scilog, Inc., generally described inU.S. Pat. Nos. 5,947,689 and 6,350,382 and U.S. Patent ApplicationPublication No. 2002/0043487. With these approaches, excessive pressurebuild-up, as well as associated leaks and bag failures are prevented.For example, when so programmed, the controller will stop all pumpingaction when a user-defined safe pressure limit is exceeded.

An exemplary solution transfer program for controlling the manifold isas follows. In a SciPro edit mode, the user enters and stores amulti-bag metering program. The following is an example of a simpleprogram to fill three, 20-liter storage bags 21, 22, 23.

Filling Program Example

000 START The following program steps are entered in an edit mode 001 CWMotor Runs Clockwise 002 RUN Motor is tuned “ON” 003 V 100000 PinchValve 41 is Energized, other pinch valves are De-energized 004 RATE: 5.0l/min Pump Rate 5 liters per minute 005 TIME: 00:04:00 Pump Runs 4minutes, Bag 21 is filled with 20 Liters 006 STOP Pump “Off”, 007 V020000 Pinch Valve 42 is Energized, other valves pinch are De-energized008 TIME: 00:00:02 2 Second Time delay 009 RUN Pump “ON” 010 RATE: 5.0l/min Pump Rate 5 liters per minute 011 TIME: 00:04:00 Pump Runs 4Minutes, Bag 22 is filled with 20 Liters 012 STOP Pump “Off” 013 V003000 Pinch Valve 43 is Energized, other pinch valves are De-energized014 TIME: 00:00:02 2 Second Time Delay 015 RUN Pump “ON” 016 RATE: 5.0l/min Pump Rate 5.0 liters per minute 017 TIME: 00:04:00 Pump Runs 4Minutes, Bag 23 is filled with 20 Liters 018 STOP Pump “Off” 019 V000000 All Pinch Valves are De-energized 020 COUNT: 1 The Program Steps000 to 020 are executed once 021 END

Changes in the RATE and TIME program steps will accommodate any storagebag volume. Additional “RUN” program blocks can be inserted to increasethe number of bags (up to 12 in the example) to be filled. However, ananalogous software program can be generated in which storage bags arefilled based upon either VOLUME or WEIGHT program commands. A scale withan appropriate capacity is required for bag filling by weight. Anoptional scale or load cell 47 can be provided to supply data to thecontroller in this regard. It will be appreciated that this embodimentmeters user-defined volumes of fluid, they automatically switches to thenext empty storage bag to be filled.

A second embodiment, which is generally illustrated in FIGS. 4-6,achieves automated preparative chromatography. In preparativechromatography, process solution containing the bio-molecule of interestis pumped through a column of gel-like particles (stationary phase)suspended in a liquid. The bio-molecule of interest specificallyinteracts (via ion-ion interactions, hydrophobic interactions, sizeexclusion, affinity, for example) with the stationary phase therebyretarding the progress of the bio-molecule through the column. Ideally,other dissolved biomaterials will interact only weakly with thestationary phase and thus will exit the column quickly.

The result is a concentration as well as a separation of thebio-molecule from the rest of the process solution matrix. Theintroduction of an elution buffer will change the local chemicalenvironment of the stationary phase, thereby causing the bio-molecule tobe released and thus able to be collected outside the column in arelatively small volume of elution buffer.

In automated preparative chromatography, the column containing thestationary phase first is washed and/or equilibrated with an appropriatebuffer solution. This wash and/or equilibration cycle is followed by aloading cycle during which the process solution is pumped through thecolumn. The bio-molecule of interest adheres to the stationary phase.The loading cycle can take many hours, depending on the process solutionvolume and pump rate with which the solution is pumped through thecolumn. The loading cycle is followed by a second wash cycle to removeany un-adsorbed biomaterial off the column.

An elution buffer then is introduced to remove the bio-molecule from thecolumn. This removal of the bio-molecule is accomplished either with astep gradient or a linear gradient. After peak collection has beencompleted, the chromatography column is regenerated and re-equilibratedusing appropriate buffer solutions as generally known in the art.

Manifold and transfer tubing assembly 48 represents a generalizedmanifold for automating preparative chromatography procedures. Inoperation, and utilizing the controller system, the exemplarypneumatically controlled pinch valve 51 is pressurized and thus opened,thereby providing access to the wash and/or equilibration buffer bag 54.At a user-definable pump rate, the wash buffer is pumped through adisposable, in-line pressure sensor 55, through a bubble trap (notshown), through the chromatography column 56, and through a detector orUV flow cell 57. On exiting the flow cell, the wash/equilibration bufferis collected in a waste container or bag 58 while pinch valve 49 ispressurized and thus open.

During the loading cycle, pinch valves 51 and 49 are opened/pressurized,while the pinch valves 52, 53 and 59 remain closed. The pump unit 45pumps the process solution through the manifold system 48, the column 56and the flow cell 57 and is collected in the waste container or bag 57.In some chromatography applications, the process solution exiting theflow cell needs to be stored separately in a “process receiving bag”(not shown) for possible re-processing. Another pinch valve (not shown)would provide access to such a “process receiving bag”.

The loading cycle is followed by a wash cycle (valves 51 and 49 areopen/pressurized, all other pinch valves are closed) which carries awayany un-absorbed material from the column to waste. By opening pinchvalves 53 and 49, elution buffer in bag 63 is introduced into the columnand is initially pumped to waste. However, when the signal from the UVdetector 57 exceeds a user-defined value, pinch valve 59 is openedthereby providing access to a peak collection bag 61 while valve 49 isclosed. On the backside of the eluted peak, valve 59 is again closed,while at the same time, valve 49 is opened.

After the material of interest has been collected in bag 61, thechromatographic column 56 requires regeneration and re-equilibration.The column regeneration process is readily automated via access toappropriate buffer solutions (not shown), which are generally as knownin the art. Depending on the underlying chromatographic complexity ofthe application, access to five or six buffer solutions may be required,and these can be provided in their own single-use bags as desired.Similarly, if multiple product peaks are to be collected, additionalpeak collection bag(s) as well as additional pinch valve(s) may have tobe incorporated into manifold and transfer tubing assembly 48.

The single-use, presterilized components of the manifold and transfertubing assembly 48, shown as a feed section, and of a second tube andbag assembly 64 for chromatographed fluid are shown in FIG. 4. Each ofthe single storage/collection bags 54, 62, 63 shown in FIG. 4 has threetube connections. The primary inlet tubing 65 consists of an asepticconnector 66 and a manual shut-off clamp 67. During solution storage,the aseptic connector is covered with an end cap to protect theconnector from contamination. The manual shut-off clamp is closed duringsolution storage.

The second tube and bag assembly 64 consists of a short piece of tubing68 connected to the bag with a closed manual shut-off clamp 68. Thesecond tubing/clamp arrangement 71 is used to relieve any gas and/orpressure build-up inside the bag during the filling operation. The thirdtube connection 72 is identical to the second tubing/clamp arrangement71 and is used as an auxiliary inlet/outlet for recirculation of the bagcontents.

The single-use storage/collection bags 58 and 61 are connected to theremaining tube manifold 72 as shown in FIG. 4 and FIG. 5. FIG. 5 showsthe relative positions of the pinch valves 51, 52, 53, 49 and 59 and theposition of the pressure sensor 55. FIG. 6 shows the insertion of themanifold tubing into the peristaltic pump head 45 as well as connectionsto the chromatography column 56 and the detector 57.

In a typical chromatography application, the single-use storage bags 54(for wash buffer), 52 (for process solution) and 63 (for elution buffer)have been previously filled, for example by using the embodiment of FIG.1-3. When the chromatography run is completed, the manual shut-offclamps on each collection bag 58 (for waste), 61 (for peak collection),and for process receiving (when desired, not shown) are closed, and theaseptic tube connections are disconnected. During storage, the asepticconnector ends are protected with end caps.

Referring further to the SciPro controller programmed for controllingthe manifold arrangement for chromatography, a mode thereof allows entryand storage of a sequence of simple commands, i.e. RUN, RATE, TIME,VOLUME, P LIMIT 1 and Valve States such as V=000000 (all pinch valvesare closed) or V=123456 (all pinch valves are open).

This controller mode is organized in subprogram blocks. The terminatingstatement of a program block can be a “VOLUME”, “TIME”, “P LIMIT D1 (orD2)” or “N LIMIT D1 (or D2)” statement. The statement “P LIMIT D1=5%”reads: “Positive Slope Signal of Detector D1 with a Threshold Value of5% Full Scale (FS)”. See the Chromatography Program Example.

Chromatography Program Example

000 START Start of 1^(st) Wash Cycle 001 CW Clockwise Motor Direction002 RUN Starts Motor 003 RATE 0.25 L/M Pump Rate During Wash Cycle 004 V100050 Wash Buffer 51 Diverted to “Waste” 49 005 VOLUME 1.0 Liters 4Minutes, End of 1^(st) Wash Cycle, TV = 1.0 L 006 RATE 1.00 L/M LoadingRate, Start of Loading Cycle 007 V 020050 Process Solution (52) Divertedto “Waste” (49) 008 TIME: 00:02:00 2 Minutes, End of Loading Cycle, TV =3.0 L 009 RATE 0.25 L/M Start of 2^(nd) Wash Cycle 010 V 100050 WashBuffer (51) Diverted to “Waste” (49) 011 VOLUME 1.0 Liter 4 Minutes, Endof 2^(nd) Wash Cycle TV = 4.0 L 012 V 003050 Elution Buffer (53)Diverted to “Waste” (49) 013 P LIMIT D1 = 5% Threshold Value DetectedStart of Peak Volume Collection 014 V 003400 Elution Buffer (53)Diverted to “Collect” (59) 015 N LIMIT D1 = 10% D1 Threshold Value, Endof Peak Volume Collection 016 V 003050 Elution Buffer (53) Diverted to“Waste” (49) 017 VOLUME 1.0 Liter Elution Volume, End of Elution, TV =5.0 L 018 RATE 0.50 L/M Start of 3^(rd) Wash Cycle 019 V 00050 WashBuffer (51) Diverted to “Waste” (49) 020 TIME 00:02:00 2 Minutes, End 0f3^(rd) Wash Cycle, TV = 6.0 L 021 STOP Pump Stops, 022 V 000000 AllV-valves Closed 023 END End of Program

For example, in line 014, the SciPro switches from “Waste” to “Collect”when the D1 signal has a positive slope and a value greater than 5% FS(line 013). The statement “N LIMIT D1=10%” reads: “Negative Slope Signalof Detector D1 with a Threshold Value of 10% FS”. In line 016, thecontroller switches from “Collect” to “Waste” when the D1 signal has anegative slope (back side of peak) and a value of 10% FS (line 15).

The user can edit and/or modify the values of: RUN, RATE, TIME, VOLUME,P LIMIT 1, N LIMIT D1 and Valve States at any time during achromatography run. User-designed application programs can be uploadedor downloaded from an external computer at any time by utilizing thecomputer's hyper terminal.

It will be appreciated that, with this embodiment, sequential schedulingof events are achieved. These include sequential scheduling of wash,load and elution cycles. The controller can initiate buffer selection,loading and peak volume collection. Typical in-line concentrationdetectors can be Wedgewood UV and/or pH detectors, which have outputs of4-20 MA outputs which can be monitored simultaneously. A typical pump isa Watson Marlow 620 R peristaltic pump head capable of generating 60 psiat a pump rate of 15 liters per minute.

User-defined detection threshold levels are used for valve switching andpeak volume collection. All solution-handling parameters, such as pumprates, column pressure, and valve positions can be monitored anddocumented in real time and can be printed out or electronicallyarchived.

In a third embodiment, automated tangential flow filtration is carriedout using a modified system designed for this use. Previously referencedU.S. Pat. No. 5,947,689 and U.S. Pat. No. 6,350,382 and U.S. PublishedPatent Application No. 2002/0043487 disclose the automation oftangential flow filtration (TFF) procedures. These are combined with theuse of disposable, single-use manifolds, which also include disposablepressure sensors and single-use, collapsible storage bags and the use ofremotely operated pinch valve(s).

A typical TFF application that utilizes a single-use, pre-sterilizedmanifold is shown in FIGS. 7-9. FIG. 7 shows the disposable,pre-sterilized components, including a tubing filtered fluid sectionhaving a permeate collection bag 81 as well as a process solution bag 82within a filtration flow-through section of the tubing. These areaseptically sealed and in a pre-sterilized (for example, irradiated)package. At the beginning of the TFF application, the permeatecollection bag 81 is empty and deflated and has been asepticallyconnected to the TFF manifold. The process solution bag was previouslyfilled, such as by using the system of FIGS. 1-3. The process solutionbag 82 is placed onto an optional scale 83 and connected aseptically tothe rest of the system. In some applications, weight information can beconveyed to the controller in carrying out the control logic.

The pre-sterilized components of this embodiment are shown in FIG. 7.The permeate collection bag 81 has three tube connections. The primaryinlet tubing 84 consists of an aseptic connector 85 and a manualshut-off clamp 86. During solution storage, the aseptic connector iscovered with an end cap to protect the connector from contamination. Themanual shut-off clamp is closed during solution storage.

The second tube connection consists of a short piece of tubing 87connected to the bag with a closed manual shut-off clamp 88. The secondtubing and clamp arrangement is used to relieve any gas and/or pressurebuild-up inside the bag during the filling operation. The third tubeconnection 89 can be identical to the second tubing and clamparrangement and is used as an auxiliary inlet and outlet forrecirculation of bag contents.

Similarly, the process solution bag 82 has three inlet and/or outlettube connections. The first tube connection 91 is used as an outlet topump solution out of the bag. The second tube connection 92 serves as areturn inlet to accommodate the re-circulated retentate. The third tubeconnection 93 again serves to relieve any excessive gas and/or pressurebuild-up inside the bag.

The permeate collection bag and the process solution bag are connectedto the filtration tube manifold, generally designated at 94 in FIG. 7.FIG. 8 shows the relative positions of the pinch valves 95 and 96 andthe position of three pressure sensors 97, 98, 99. FIG. 9 shows theinsertion of the manifold tubing into the head of the peristaltic pumpunit 45.

Prior to starting the pump unit 45, all of the manual shut-off clampsare opened except those clamps that relieve any gas and/or pressurebuild-up inside the bags. Initially the valve 95 is closed and the valve96 is open, while the pump unit 45 starts to recirculate the solutioncontained in the process solution bag 82 through a tangential flowfilter system 101. The air volume contained in the tubing and tangentialflow filter system 101 ends up in the process solution bag 82 where itis vented to the outside through a sterilizing air filter (not shown).Once the optimal pump recirculation rate has stabilized, pinch valve 95is opened and permeate is collected.

The micro filtration or ultra filtration can be carried out either byconstant rate or by constant pressure. Software programs which aresuitable to automate the filtration process through the use of thecontroller 46 are described in U.S. Pat. Nos. 5,947,689 and 6,350,382and U.S. Patent Application Publication No. 2002/00434487.

The forth, fifth, and sixth embodiments, which are generally illustratedin FIG. 10, FIG. 11, and FIG. 12, respectively, are similar in manyrespects to the first three embodiments illustrated in FIGS. 1-9.However, the systems shown FIGS. 10-12 include at least one conductivitysensor. Any available conductivity sensor may be used with thesesystems, for example, toroidal sensors. In keeping with the invention,the conductivity sensor is a pre-sterilized, single-use, disposable,in-line sensor. The embodiment shown in FIG. 13 is a sensor withelectrodes.

FIG. 10 shows an aseptic solution transfer system similar to the systemof FIGS. 1-3 and like numbers designate like components. However, inthis embodiment the in-line pressure sensor 32 is replaced with adisposable in-line conductivity sensor 102. During operation, thesolution moves from the vat or reservoir 44 through the sensor 102, thefilter 33, and then is serially diverted into the single use storagebags, 21, 22 and 23. The pinch valves 41, 42, and 43, as describedabove, may be included as desired and may be operated remotely to closethe lines into each storage bag and typically will be pneumatically orelectrically activated.

The conductivity sensor monitors the conductivity levels of thesolution. The levels are reported back either to a user interface, whichdisplays the information, or to the manifold controller 46. Based on theinformation provided by the conductivity sensor or sensors, the manifoldcontroller 46 (or the user interface in some embodiments) may thenmodify the operation of the pump unit 45, open and close the variouspinch valves, start user-determined programs, or stop user-determinedprograms.

The fifth embodiment is generally illustrated in FIG. 11 and is utilizedto achieve automated preparative chromatography. As stated above, inpreparative chromatography, a process solution containing thebio-molecule of interest is pumped through a column of gel likeparticles (stationary phase) suspended in a liquid. The bio-molecule ofinterest interacts with the stationary phase while the otherbio-molecules in the process solution will quickly exit the column. Themanifold and transfer tubing-assembly 48 represents the generalizedmanifold system as shown in FIGS. 4-6. Unlike the system shown in FIGS.4-6, the fifth embodiment replaces the in-line pressure sensor 55, thedetector 57, or both with an in-line conductivity sensor 155, 157.

The conductivity sensors monitor the conductivity levels of the solutionentering the chromatography column 56 and the conductivity levels as thesolution leaves the column. The levels are reported back either to auser interface, which displays the information, or to the manifoldcontroller 46. Based on the information provided by the conductivitysensors, the manifold controller 46 (or the user interface in someembodiments) may then modify the operation of the pump unit 45, open andclose the various pinch valves, start user-determined programs, or stopuser-determined programs.

The sixth embodiment, shown in FIG. 12, demonstrates how conductivitysensors may be used in conjunction with a system designed to performautomated tangential flow filtration. The sixth embodiment has the sameoverall configuration as the system shown in FIGS. 7-9, with theaddition of an in-line conductivity sensor 158 which is positioned afterthe pressure sensor 98 and before the pinch valve 96.

The conductivity sensors monitor the conductivity levels of the fluidpassing to the process solution bag 82. The conductivity levels arereported back either to a user interface, which displays theinformation, or to the manifold controller 46. Based on the informationprovided by the conductivity sensors, the manifold controller 46 (or theuser interface in some embodiments) may then modify the operation of thepump unit 45, open and close the various pinch valves, startuser-determined programs, or stop user-determined programs. Theconductivity sensor 158 is useful in TFF as it monitors theconcentration or absence of molecules passing through the tubing to theprocess solution bag 82. For example, if, the conductivity sensormeasures abnormally high conductivity levels during the cleaning oroperation of the tangential flow filter, it may signal to the controlleror user that the filter is defective. On the other hand, if theconductivity sensor measures abnormally low conductivity levels duringthe cleaning or operation of the tangential flow filter, it may signalthat the filter or tubing is clogged.

The preferred embodiment of an in-line conductivity sensor has twocomponents: the user interface or the controller 46 and the disposablesensor assembly module. Further description of the in-line, single-useor disposable conductivity sensor are found in copending applicationSer. No. 11/294,296, filed simultaneously with the present Applicationon Dec. 5, 2005 and entitled “Disposable, Pre-Calibrated, Pre-ValidatedSensors for use in Bio-processing Applications,” now U.S. Pat. No.7,857,506, incorporated hereinto by reference. However, in otherembodiments, the functionality of each component may be combined with ormoved to the other component.

The disposable sensor assembly module, generally designated as 200 inFIG. 13, contains inexpensive components. Typically, the sensor assemblymodule contains a short tubular fluid conduit 202 and a sensing portion,generally designated as 201, which includes electrodes 203, a printedcircuit board (PCB) 204 and a sensor-embedded non-volatile memory chip(not-shown). In this embodiment, four electrode pins 203 arepress-fitted through four linearly arranged holes in the fluid conduitwall 202, and are placed in the pathway of fluid progressing through thesystem that is connected at both ends of the fluid-conduit 202. Theelectrodes 203 and holes are epoxied, connected or sealed into place toprevent leaks or contamination. The PCB 104 is enclosed in a sheath 205.To prevent contamination and to make the assembly 201 impervious to anyliquid, the combination of the sheath 205, PCB 204, electrodes 203 andto some extent the fluid conduit 202 is sealed in an exterior housing206.

Toroidal conductivity sensors may be used in place of the electrodes inthe sensor assembly 202. The toroids of the toroidal sensors may bearranged in a non-obtrusive manner around the fluid circuit. Typically,two toroids are used. One toroid is used to “drive” or induce a currentthrough the fluid, while the other “senses” or measures the inducedcurrent through the fluid.

The electrodes or toroids are connected to the PCB 204. The PCB maycontain various components, such as a thermistor to measure thetemperature of the fluid in the fluid circuit 202 or a non-volatilememory chip or EEPROM. The PCB is connected to a user interface, controlunit, or controller 46. The controller 46 or user interface connects toand accesses the PCB 204, its components, and the electrodes 203 by aplug-in wires or leads (not shown).

The controller 46 or the user interface produces the current that drivesthe electrodes or toroids and measures the conductivity by measuring thecurrent on the “sensing” electrodes or toroids. The conductivity of thefluid passing through the fluid conduit is measured by driving a currentthrough one or more electrodes, and then using the remaining electrodesto measure the current that passes through the fluid. The current or thevoltage drop measured is proportional to the conductivity of the fluidpassing through the fluid conduit.

The user interface or controller 46 may access calibration informationstored in the non-volatile memory of the sensor. During production ofthe disposable sensors 200, small variations in the design and placementof the electrodes 203 as well as variations in the accuracy of thethermistors may lead to inaccurate conductivity measurements. However,each sensor is individually calibrated to account for the adverseeffects due to these small variations. The sensor specific calibrationinformation is stored in the non-volatile memory of the sensor.

This calibration information may include a temperature offset and aconductivity constant. The temperature offset represents the lineardifference between the known temperature of the fluid and thetemperature measure by the sensor at the time of calibration. Theconductivity constant represents the difference between the knownconductivity of the fluid and the conductivity measure by the sensor atthe time of calibration. When measuring the conductivity of the fluid inthe fluid conduit, the user interface or controller 46 will retrieve thecalibration information to use in the calculations for conductivity. Thetemperature offset and conductivity constant are later utilized by theuser interface or controller 46 to calculate the actual conductivity ofthe biotechnology fluid passing through the fluid conduit 202.

The calibration information may also include information about themethod of calibration, the statistical variance among different sensorsin the same lot, and the date when the sensor was last calibrated.

In addition to the calibration information, production information maybe stored in the non-volatile memory on the sensor. Productioninformation may include items such as the date, time, or lot number forwhen the sensor was manufactured.

FIG. 14 shows a possible embodiment of a user interface, as generallydesignated 210. As stated above, the sensor 200 may be connected toeither the controller 46 or a user interface 210. While both the userinterface 210 and the controller 46 may provide the same functions anddisplay similar information, the embodiment of user interface 210 inFIG. 14 may be advantageous. The user interface 210 is somewhat moreportable in comparison to an entire manifold system or controller 46,may be utilized separately from the entire system, and allows for eitherthe user interface or components of the system to be independentlyupgraded or replaced. Other embodiments might replace the controller 46,with the user interface 210. In these embodiments, the smaller userinterface 210 also has control logic to receive data from the system andto operate the various valves and pumps. In keeping with the invention,the terms user interface and controller may be used interchangeably.

The user interface 210 has a display 211 and several input keys on itsface. These keys include the Menu key 222, the Up key 223, the Down key224, the Re-Cal key 225, the Enter key 226, the Exit key 227 and theSensor On/Sensor Standby key 228. To turn the user interface on, theuser must press the Sensor On key 228. During normal operation, thedisplay 211 typically reports the conductivity of the fluid beingmeasured by the system in Siemens, the temperature of the fluid indegrees Centigrade, the percent of total conductivity, and a graphicalrepresentation of the percent of total conductivity.

The Menu key 222 allows users to progress through different menus asshown in FIG. 15. The display screen 221 initially presents “RUN” screen230, which typically displays the conductivity of the fluid beingmeasured by the system in Siemens, the temperature of the fluid indegrees Centigrade, the percent of total conductivity, and a graphicalrepresentation of the percent of total conductivity. If the userrepeatedly presses the Menu key 222, the screen 221 will display theHigh Conductivity Value 231 (for example 80,000 μS) and then the LowConductivity Value 232 (for example 0 μS). If the user continues topress the Menu Key 222, the user interface 220 will display thecalibration information retrieved from the non-volatile memory of thesensor.

The user interface does not necessarily have to use the calibrationinformation stored on the sensor. In the illustrated embodiment, theuser may modify the calibration information utilized by the userinterface 220 without permanently modifying the information stored inthe non-volatile memory on the sensor. The user may manually change thecalibration information utilized by the user interface 220 by selectingthe Up or Down arrow keys 223, 224 when presented with the correspondingscreen.

The modifiable calibration information may include the ReferenceTemperature 233, the Temperature Coefficient 234, and the TemperatureOffset 235. By pressing the Menu Key 222, the user may modify by usingthe Up or Down arrow keys 223, 224 the units in which conductivity isdisplayed 236, the setting for the serial port 237, the different printtimes for the print option 238, the maximum conductivity measurement atwhich point the user interface 220 produces a high audible alarm 239 orlow audible alarm 240. The user may also select to restore or re-installthe factory calibration values 241, or change the date 242 and time 243.When presented with any of the above mentioned options, the user mayreturn the user interface to normal operations without changing theoption by pressing the Exit Key 227.

The user may also re-calibrate the sensor or overwrite the calibrationinformation stored in the non-volatile memory chip by selecting theRe-cal key 225, which runs the recalibration program. As shown in FIG.16, the recalibration program displays the calibration information onthe display screen 221. The user can scan through the calibrationinformation by using the Up and Down arrow keys 223, 224. By pressingthe Menu key 222, the user may select a specific piece of calibrationinformation, such as the Pump Low Calculation solution 244, ExternalCalibration Data 245 and 246, and the High Pump Calibration 247, 248,and 249. The user may then modify the value for each piece ofcalibration information by selecting the Up or Down keys 223, 224.

After the information is modified, the new value overwrites the storedinformation in the non-volatile memory of the sensor when the userpresses the Enter Key 225. The display 211 will then report the currentreadings 250 as computed using the new calibration information. In thefuture, when the user selects “Factory Reset” 241, the current settingsof the user interface are replaced with those values entered by the userduring the last recalibration program. However, if the user wants to endthe recalibration program without changing the options, he or she needonly press the Exit key 227.

The user interface 220 may also include a sensor key (not shown). Asshown in FIG. 17, when the user presses the Sensor key, the userinterface retrieves the production information and calibrationinformation stored in the non-volatile memory of the sensor. Thecalibration information may include information that was replaced by therecalibration program. Initially, this operation displays the unique IDnumber for the sensor 251. By pressing the Menu key 222, the user mayview other calibration information 252, such as the type of solutionused during calibration as shown, the temperature of the calibrationsolution, and the statistical information for the sensor. The user mayalso view the date when the sensor was last calibrated or recalibrated253. The user may return the user interface to normal operations 254 bypressing the Exit Key 227.

FIG. 13 shows the top view or the component view of the sensor 200. Theelectrodes 203 are connected to the underside of the PCB 204. Asurface-mounted thermistor is in thermal contact with two of theconductivity electrode pins when four are provided. A second, importantfunction of the thermistor is to act as a pull-up resistor for thenon-volatile memory chip, thereby assuring proper functioning of thememory device. The thermistor is used to monitor the temperature of thesolution in the fluid conduit 202, via thermal conductance, such beingtransmitted to the user interface 210. The user interface 210 reportsthe solution temperature data and utilizes the temperature data tocorrect or normalize the solution conductivity reading.

A sensor-embedded non-volatile memory chip or an EEPROM is mounted onthe surface of the PCB 204. The non-volatile memory chip or EEPROM isused to store sensor-specific information. This information can becalled up, displayed and printed out, on demand, by the user interface210.

The sensor-specific information is electronically entered into thenon-volatile memory chip during factory calibration of the conductivitysensor 200. The sensor-specific information may include the following:Cell Constant (K), Temperature Offset, the unique Device ID, and theCalibration Date, the production lot number of the sensor, theproduction date of the sensor, the type of fluid used for calibration,the actual temperature of the fluid used, and “out-of-box” sensorperformance value.

During production, small differentiations in the electrodes 203, therespective angles of the electrodes, and the gaps between the individualelectrodes will result in different conductivity readings for eachsensor produced. These differences can significantly affect accuracy. Inkeeping with the invention, these differences are successfully addressedby having each sensor normalized or calibrated as a part of itsmanufacturing procedure.

In the illustrated example, each conductivity sensor 108 is calibratedusing certified 0.100 molar KCl (potassium chloride) solution maintainedat 25.0° C. The conductance, which is dependent on the cell geometry andthe solution resistivity, is determined by measuring the voltage dropacross the electrodes. The measured conductance together with knownsolution conductivity allows the calculation of the sensor-specific CellConstant (K). The Cell Constant (K) is determined by the followingequation:[Solution Conductivity,(S/cm)]/[Conductance(S)]=[Cell Constant,K,(cm⁻¹)]The sensor-specific Cell Constant (K) is then stored in the non-volatilememory of the conductivity sensor 200.

For example, the solution conductivity for a 0.100 molar KCl solution isknown to be 12,850 μS (or 0.01285 S) at 25.0° C. The typical measuredconductance for a 0.100 molar KCl solution using a sensor with a ⅛ inchLuer conductivity cell with a 0.10 inch electrode separation is 0.0379Siemens. Using the equation above, the corresponding Cell Constant (K)for the particular disposable sensor of this illustration is calculatedto be 0.339 cm⁻¹.

Once the Cell Constant (K) is calculated it is stored on the sensor. Theuser interface will recall the Cell Constant (K) from the sensor. Whenundergoing normal operations, the user interface 210 measures theconductance in Siemens of the solution flowing through the fluid conduit202 by passing a current through the electrodes 203 and measuring thecurrent across the two inner electrodes 203. The user interface 210 willthen use the Cell Constant (K) for this particular disposable sensor todetermine the electrical conductivity of the solution flowing throughthe fluid conduit. The user interface calculates the solution'selectrical conductivity by multiplying the measured conductance by theCell Constant (K), as demonstrated in the following equation:[Cell Constant,K,(cm⁻¹)]×[Conductance(S)]=[Solution Conductivity,(S/cm)]The sensor, once calibrated, provides a linear response for NISTtraceable standard solutions ranging from 1 to 200,000 μS.

The temperature of a solution will also affect its electricalconductivity. As a result, the sensor must also measure and account forthe temperature of the solution to achieve an accurate electricalconductivity measurement. Ordinarily, un-calibrated thermistors willhave a variance of ±5% between their measured reading and the actualtemperature. A calibrated thermistor may achieve a variance of ±11% orless.

In this regard, a sensor-specific Temperature Offset is calibrated atthe factory. To determine the Temperature Offset, temperature readingsare made while a 25.0° C. KCl solution is pumped through the fluidconduit and over the electrodes. A comparison is then made between thetemperature reading of the un-calibrated thermistor on the sensor (Tsen)with that of a NIST-traceable thermometer or thermistor (Tref). Thedifference between the two readings is the Temperature Offset(Tref−Tsen=TempOffset). The Temperature Offset may have either apositive or a negative value. The sensor-specific Temperature Offset isthen stored in the non-volatile memory on the sensor.

Each sensor has an “out-of-box” performance variance value which is alsostored on the sensor, typically in the non-volatile memory chip. This“out-of-box” value is a statistically derived performance variance(measured in 0.100 molar KCl at 25.0° C.) that represents the maximummeasurement error for that specific sensor within a 98% confidencelimit. The statistically derived variance value is based on theperformance analysis of all calibrated sensors within a production run,typically of between about 100 and about 500 sensor assemblies. Thefactory determined performance variance represents a predictive,“out-of-box” sensor performance level. This statistical treatment isanalogous to and representative of a sensor validation procedure.Factory pre-validated conductivity sensors are thereby provided. Themeaning of “pre-validated” is further illustrated herein, including asfollows.

In the preferred embodiment, each conductivity sensor undergoes twofactory measurements. The first measurement involves sensor calibrationand determination of the specific Cell Constant (i.e. response factor)using a 0.100 molar KCl solution at 25.0° C. as described herein. Inanother separate and distinct measurement with 0.100 molar KCl solutionat 25.0° C., the solution conductivity is experimentally determinedusing the pre-calibrated sensor. When taking into account theexperimentally derived solution conductivities for all pre-calibratedsensors, the mean conductivity value closely centers around thetheoretical value of 12,850 μS with a 3-sigma standard deviation of+/−190 μS or +/−1.5% An operator may access this information via theuser interface 210 or Conductivity Monitor.

In addition to the calibration information, such as the Cell Constant(K) and the Temperature Offset, the sensor-specific Device ID,Calibration Date, and statistical information are stored in thenon-volatile memory. The Device ID is stored as a string of numbers, forexample: nn-ss-xxxx-mmyy. In this example, the variables represent thesensor lot number (nn), fluid conduit size (ss), the device serialnumber (xxxx) and the manufacturing date by month and year (mmyy). Forexample, sensor containing the Device ID of 02-02-0122-1105 means thatthis sensor was the 122^(nd) sensor made in lot 02 of conduit size 02 (afluid conduit with a diameter of ⅜″ or 9.5 mm having a barb connector),manufactured in November of 2005. In this illustration, thesensor-specific Calibration Date or the date on which the sensor wascalibrated using 0.100 molar KCl solution at 25.0° C. is also stored inthe sensor's non-volatile memory as a separate data entry.

Additionally, statistical information or statistical data about theentire lot may also be stored in the non-volatile memory. For example,the average cell constant for lot 122 may be stored in the non-volatilememory of each sensor in lot 122. The standard deviation for cellconstants for each lot may also be stored (i.e. “out-of-box” variancevalue) in the non-volatile memory of each sensor produced in that lot.This allows the user to determine whether a particular sensor is withinthe statistical range to achieve the proper margin of error for aspecific experiment or bio-processing operation. As those skilled in theart will appreciate, other known statistical methods may be utilized,the results of which may be stored in the non-volatile memory on thesensing device.

In addition to storing the Cell Constant (K), Temperature Offset, DeviceID, the Calibration Date, and other information in the non-volatilememory on the sensor, a summary of this information may be printed onthe outside of the sensor. This information may be consulted by theuser, used to later re-calibrate the sensor, and allows the user toinput the printed information directly into the user interface.

It will be understood that the embodiments of the present inventionwhich have been described are illustrative of some of the applicationsof the principles of the present invention. Numerous modifications maybe made by those skilled in the art without departing from the truespirit and scope of the invention.

The invention claimed is:
 1. A manifold system for biotechnology uses,comprising: a manifold unit which is pre-sterilized and disposable so asto be adapted for single-time usage, including: at least one length oftubing having at least one inlet end portion, at least one outlet endportion, an outside surface, and an inside surface which is sterilizedfor passage of a biotechnology fluid therethrough; at least onesingle-use container operatively connecting to said length of tubing atleast one pre-sterilized, calibrated and disposable electricalconductivity sensor adapted for single-time usage; the sensor has amemory component capable of storing data, the memory component includinga sensor-specific Cell Constant (K) assigned to that specific sensorduring calibration of the sensor; the memory component further includesa sensor-specific temperature offset assigned to that specific sensorduring calibration of the sensor, wherein said temperature offset wasdetermined during manufacture employing a calibration solution,including determining the actual temperature (Tref) value of thecalibration solution, using the specific pre-calibrated sensor tomeasure the temperature (Tsen) value of the calibration solution, andmathematically combining said Tref and said Tsen into saidsensor-specific temperature offset; and wherein the disposableelectrical conductivity sensor senses electrical conductivity of thebiotechnology fluid.
 2. The manifold system in accordance with claim 1,further including further including at least one valve remotely operablein response to a signal remote from said valve, said valve engages saidlength of tubing at a discrete location therealong, said valveindependently selectively allowing or stopping flow of the biotechnologyfluid through said inside surface of the length of tubing at saiddiscrete location for that valve.
 3. The manifold system in accordancewith claim 2, wherein the container is bag, and the valve is a pinchvalve that engages the outside surface of the length of tubing.
 4. Themanifold system in accordance with claim 1, wherein said disposableelectrical conductivity sensor is comprised of: a conduit for directingbiotechnology fluid therethrough, said conduit being connectable to atleast one said length of tubing; and a sensing portion, said sensingportion being arranged for sensing the electrical conductivity of thebiotechnology fluid.
 5. The manifold system in accordance with claim 4,further including a user interface unit, and wherein said disposableelectrical conductivity sensor is electrically connected to said userinterface unit.
 6. The manifold system in accordance with claim 5,wherein said user interface unit includes control logic that dictates orcontrols, at least in part, the external operations on said manifoldsystem.
 7. The manifold system in accordance with claim 6, furthercomprising a flow imparting unit that engages at least one length oftubing, said flow imparting unit, at least in part, being controlled bythe user interface unit, whereby the user interface unit performs anoperation on the manifold system by engaging or stopping the flowimparting unit.
 8. The manifold system in accordance with claim 7,wherein the container is bag, the valve is a pinch valve that engagesthe outside surface of the length of tubing, the flow imparting unit isa pump, and the control logic controls or dictates the timing of openingand closing of the remotely operable pinch valve.
 9. The manifold systemin accordance with claim 6, further comprising one or more valves, atleast one of which is remotely operable, wherein said user interfaceunit controls operation of said valve, said user interface unit havingcontrol logic which controls or dictates the timing and the extent ofopening and closing of said remotely operable valve, whereby the userinterface unit performs an exterior operation.
 10. The manifold systemin accordance with claim 6, wherein said user interface unit controlsthe external operation of the manifold system in response to theconductivity of the biotechnology fluid passing through saidconductivity sensor.
 11. The manifold system in accordance with claim 6,wherein said user interface unit measures the conductivity of thebiotechnology fluid passing through the conduit by driving a currentthrough the sensing portion of the conductivity sensor.
 12. The manifoldsystem in accordance with claim 1, further including a disposablepressure sensor positioned along said tubing such that the biotechnologyfluid flows therethrough at a location upstream of said outlet endportion.
 13. The manifold system in accordance with claim 1, whereinsaid system is for automated preparative chromatography, wherein: saidtubing is in at least two sections including a chromatography feedsection and a chromatographed fluid section, said chromatography feedsection has an outlet and a plurality of serially arranged inletpassageways for operable connection with said single-use container, andsaid chromatographed fluid section has an inlet and said outlet endportion of the tubing which has a plurality of serially arranged outletpassageways for operable connection with said single-use container; andfurther comprising a chromatography column between said chromatographyfeed section and said chromatographed fluid section.
 14. The manifoldsystem in accordance with claim 13, wherein said disposable conductivitysensor is disposed downstream of the chromatography column.
 15. Themanifold system in accordance with claim 13, wherein said disposableconductivity sensor is disposed upstream of the chromatography column.16. The manifold system in accordance with claim 13, further including auser interface unit, and wherein said disposable conductivity sensor iselectrically connected to said user interface unit.
 17. The manifoldsystem in accordance with claim 16, wherein said user interface unitcontrols the external operation on the manifold system in response tothe conductivity of the biotechnology fluid passing through saidconductivity sensor.
 18. The manifold system in accordance with claim17, further comprising a flow imparting unit that engages at least onelength of tubing, said flow imparting unit, at least in part, beingcontrolled by the user interface unit, whereby the user interface unitperforms an exterior operation on the manifold system by engaging orstopping the flow imparting unit.
 19. The manifold system in accordancewith claim 17, further comprising one or more valves, at least one ofwhich is remotely operable, wherein said user interface unit controlsoperation of said valve, said user interface unit having control logicwhich controls or dictates the timing of changes in the extent ofopening and closing of said remotely operable valve, whereby the userinterface unit performs an exterior operation.
 20. The manifold systemin accordance with claim 19, wherein the container is bag, the valve isa pinch valve that engages the outside surface of the length of tubing,the flow imparting unit is a pump, and the control logic controls ordictates the timing of opening and closing of the remotely operablepinch valve.
 21. The manifold system in accordance with claim 1, whichsaid system is for tangential flow filtration, wherein one said singleuse container is a process solution container and another single-usecontainer is a permeate collection container; said tubing is in at leasttwo sections including a filtration flow-through section and a filteredfluid section, said filtration flow-through section includes saidprocess solution container; said filtered fluid section includes saidpermeate collection container operatively connected to the tubing, andfurther comprising: a disposable filter between said filtrationflow-through section and said filtered fluid section, whereby fluid fromsaid process solution container is filtered through said disposablefilter and is collected in said permeate collection container.
 22. Themanifold system in accordance with claim 21, further including a userinterface unit, and wherein said disposable electrical conductivitysensor is electrically connected to said user interface unit, said userinterface unit containing control logic that receives and interpretssignals from the conductivity sensor.
 23. The manifold system inaccordance with claim 22, wherein said disposable electricalconductivity sensor is positioned along a location downstream of saiddisposable filter, said conductivity sensor being connected to said userinterface unit whereby the user interface unit monitors the electricalconductivity of the fluid within said tubing.
 24. The manifold system inaccordance with claim 22, further comprising one or more valves, atleast one of which is remotely operable, wherein said user interfaceunit controls operation of said valve, said user interface unit havingcontrol logic which controls or dictates the timing and the extent ofopening and closing of said remotely operable valve, whereby the userinterface unit performs an operation.
 25. The manifold system inaccordance with claim 24, wherein the container is bag, the valve is apinch valve that engages the outside surface of the length of tubing,the flow imparting unit is a pump, and the control logic controls ordictates the timing of opening and closing of the remotely operablepinch valve.
 26. The manifold system in accordance with claim 22,wherein said user interface unit includes control logic which dictatesor controls, at least in part, the external operations on said manifoldsystem.
 27. A manifold system for biotechnology uses, wherein saidsystem is for automated, aseptic fluid transfer, comprising: a manifoldunit which is pre-sterilized and disposable so as to be adapted forsingle-time usage, including: at least one length of tubing having atleast one inlet end portion, at least one outlet end portion, an outsidesurface, and an inside surface which is sterilized for passage of abiotechnology fluid therethrough; at least one single-use containeroperatively connecting to said length of tubing; said outlet end portionof the tubing operably connects with said single-use container; at leastone pre-sterilized, calibrated and disposable electrical conductivitysensor adapted for single-time usage, the sensor having a memorycomponent capable of storing data, the memory component including asensor-specific Cell Constant (K) assigned to that specific sensorduring calibration of the sensor; the memory component further includesa sensor-specific temperature offset assigned to that specific sensorduring calibration of the sensor, wherein said temperature offset wasdetermined during manufacture employing a calibration solution,including determining the actual temperature (Tref) value of thecalibration solution, using the specific pre-calibrated sensor tomeasure the temperature (Tsen) value of the calibration solution, andmathematically combining said Tref and said Tsen into saidsensor-specific temperature offset; and wherein the disposableelectrical conductivity sensor senses electrical conductivity of thebiotechnology fluid.
 28. The manifold system in accordance with claim27, further including a plurality of valves, at least one of which isremotely operable in response to a signal remote from said valve, eachsaid valve engages said length of tubing at a discrete locationtherealong, each said valve independently selectively allowing orstopping flow of the biotechnology fluid through said inside surface ofthe length of tubing at said discrete location for that valve.
 29. Themanifold system in accordance with claim 27, wherein said disposableconductivity sensor is comprised of: a conduit for directingbiotechnology fluid therethrough, said conduit being connectable to atleast one said length of tubing; and a sensing portion, said sensingportion being arranged for sensing the electrical conductivity of thebiotechnology fluid.
 30. The manifold system in accordance with claim28, wherein the container is bag, and the valve is a pinch valve thatengages the outside surface of the length of tubing.